Immune reconstitution inflammatory syndrome in natalizumab-associated PML

We agree with Hellwig et al. that prospective and critical analysis of the benefits and risks of PLEX/IA is highly desirable. The practical aspects of such investigations are extremely challenging, particularly because clinically significant inflammatory responses to PML are difficult to quantify, and are occurring in some cases even before contrast enhancement is detected on MR scans. Consequently, it is not possible to know whether JC virus driven oligodendrocyte lysis giving advancing PML or a damaging inflammatory response is causing progressive symptoms and changes on MR scans. While the improved survival in PML cases in natalizumab associated PML support the current recommendations to routinely provide PLEX to remove natalizumab and activate immune surveillance in the brain, it would be very useful to develop the means to select populations where more gradual immune reconstitution might be preferred.

For disclosures, contact the editorial office at [email protected].

Tan et al. [1] postulated that early immunological rebound in natalizumab-associated PML may implicate a worse outcome and survival. Unfortunately, the interval between the last natalizumab infusion and PLEX/IA was not provided.

Although it did not reach significance, the time between onset of symptoms and PML diagnosis was about 75% longer in those with the early PML-IRIS, which may contribute to a worse outcome. We treated 12 German PML and observed IRIS in all patients after PLEX/IA, but also a considerable extension of the PML lesions with development of new PML lesions in at least 4 patients. None of our 12 patients died, but one developed severe clinical deterioration and the MRI showed expanding PML lesions (without Gd enhancement in the first MRI). While IRIS seemed to be "controllable" in all our patients with repetitive pulses of corticosteroids, the only successful treatment of PML itself is to restore immunocompetence, which is more easily achieved in natalizumab-PML than in the setting of HIV-associated PML.

Therefore, a clinical, immunological, and radiological risk stratification for development of severe IRIS or PML deterioration is necessary to determine if there are subgroups that may profit from PLEX/IA or those who may deteriorate. Prospective studies investigating the role of PLEX/IA in the subgroup of those with Gd enhancement at the time of PML diagnosis could be helpful.

1.Tan IL, McArthur JC, Clifford DB, Major EO, Nath A. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology 2011; 77:1061-1067.

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We thank the authors for their suggestions on how to better define the two different forms of PML- IRIS. We attempted to develop terminology that could be used for not only for patients with multiple sclerosis who develop PML but other immune compromised states such as HIV infection or organ transplants. Typically, in immune suppressed individuals who develop PML, there is no evidence of inflammation so any inflammation in the early or late stage is a form of immune reconstitution. Furthermore, PML-IRIS is not always a radiological diagnosis. The enhancement associated with PML-IRIS on the MRI scan can be very subtle or not noticeable to the naked eye particularly in HIV-infected and organ transplant patients. [2] Hence we prefer the term "early PML-IRIS" to define individuals who have evidence of IRIS at the time of diagnosis of PML and "delayed PML-IRIS" to define individuals who were known to have PML but develop IRIS later in the course of the illness usually associated with an improvement of the underlying immune dysfunction.

2. Harrison DM, Newsome SD, Skolasky RL, McArthur JC, Nath A. Immune reconstitution is not a prognostic factor in progressive multifocal leukoencephalopathy. J Neuroimmunol. 2011 Sep 15;238:81-86.

For full disclosures, see original article.

The authors identified early-PML-IRIS based on gadolinium enhancement in the lesions on brain MRI at the time of PML diagnosis, before natalizumab withdrawal. Early-PML-IRIS occurred when (approximately 19 days after the last natalizumab infusion) [1] natalizumab effect on alpha4-integrin binding remained optimal. [2] Hence, inflammatory MRI signs of the so- called early-PML-IRIS take place in the absence of ongoing restoration of the immune competence within the brain. This is obviously different from what is seen in HIV-related PML where IRIS occurs only after inducing the immune reconstitution through the initiation of anti-retroviral therapy. [3]

Early-PML-IRIS in natalizumab-associated PML may only represent radiological signs of BBB alteration due to JC virus infection in this specific context. The operational definition of early-PML-IRIS should rather be early Infection-Related or Idiopathic Radiological Inflammatory Syndrome as opposed to the delayed IRIS, which truly reflects an immune reconstitution. The prognostic factors, responsiveness to steroid administration and to plasma exchanges should then be evaluated separately for these two distinct conditions.

1. Tan IL, McArthur JC, Clifford DB, Major EO, Nath A. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology 2011.

2. Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009;72:402-409.

3. Tan K, Roda R, Ostrow L, McArthur J, Nath A. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 2009;72:1458-1464.